Abstract

Non-alcoholic fatty liver disease (NAFLD) and its more advanced form non-alcoholic steatohepatitis (NASH), are the most common chronic liver diseases in developed countries. Moreover, NAFLD and NASH are considerable risk factors for atherosclerosis, the most frequent vascular pathology in these and other metabolic diseases. Despite this strong connection, current knowledge of the relationship between NAFLD/NASH and atherosclerosis is scarce. Recently, we studied hyperlipidemic Apoe knockout mice with Endothelial-Specific gain of Transient Receptor Potential Canonical 3 channel function (TgESTRPC3/ApoeKO) and found that these animals had increased burden of advanced aortic atherosclerosis (16 weeks on high fat diet) compared to non-transgenic ApoeKO littermate controls (non-Tg/ApoeKO), whereas early lesions (10 weeks on high fat diet) were not different. Here, we report that at the early stage when differences in aortic atherosclerosis are not yet manifest, the livers of TgESTRPC3/ApoeKO mice show steatosis, fibrosis and altered hepatic enzymes compared to non-Tg/ApoeKO animals. Because differences in liver pathology were noticeable long before differences in atherosclerosis were evident, our studies suggest that TRPC3-related endothelial mechanisms that promote steatohepatitis may also contribute to atherosclerosis progression. In vitro, downregulation of TRPC3 in liver sinusoid endothelial cells reduces their susceptibility to ER stress-induced apoptosis, suggesting that a pro-apoptotic effect of TRPC3 may add to other fibrogenic factors in vivo. These novel findings show a positive association between augmented expression of an endothelial TRPC channel, development of early steatohepatitis and atherosclerotic burden in a hyperlipidemic mouse model of NAFLD fed conventional western-type diet.